17-diacetals of estrone



ilted States l atent 2,940,990 17-DIACETALS F ESTRONE Esteban Volkov and George Rosenkranz, Mexico City, Mexico, assignors to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed May 22, 1956, Ser. No. 586,370 7 Claims. (Cl. 260*3975) The present invention relates to a process for the production of cyclopentanophenanthrene derivatives and to certain novel intermediates utilized in the process.

More particularly, the present invention relates to a novel process for the production of 3-lower alkoxy 19- nor-A -androstad.iene-l7-one derivatives, and especially the corresponding B-methoxy compound, as well as to certain novel intermediates for the production of these compounds.

3-methoxy 19 nor A -androstadiene-l7-one is a known intermediate which may be easily transformed into the valuable progestational' hormone A -19-nor-17- ethinyl-androstene-l7fi-o1-3-one (l9 nor-ethinyltestosterone) which is disclosed in United States Patent No. 2,744,122, granted May 1, 1956. Although there is disclosed in this United States patent a process for the production of a l9-nor-ethinyltestosterone, there has been discovered in accordance with the present invention a more eflicient process utilizing as a starting material estrone and involving preparation of the novel l7 -diacetal of estrone, the conversion of the l7-diacetal of estrone into the corresponding 3-lower alkoxy derivative, the reduction of the aromatic system in Ring A to a diene system by reaction with an alkali metal in solution in liquid ammonia, and finally the selective hydrolysis of the novel l7-diacetal of the 3-lower alkoxy 19-nor-A -androstadiene-17-one to produce the known intermediates, namely the 3-lower alkoxy derivatives of 19-nor-A androstadiene-17=one. These last compounds and especially the 3-rnethoxy compound, as is known, may be provided with a 17a-ethinyl group by reaction with acetylene in the presence of potassium tamylate and thereafter subjected to the action of a dilute acid to hydrolyze the methoxyl group at C-3 and simultaneously cause migration of the double bond to form the A -3-keto system of l9-nor-l7-ethinyltestosterone.

The following equation serves to illustrate-the process of the present invention and the production of the novel intermediates hereinbefore referred to:

ethyl orthoiormate ether i formation 0 Et on: &0 Et 2-30 Et i l r alkali metal i T i R 0 liquid ammonia R0 V selective hydrolysis Patented June 14, 1960 In the above equation R represents a lower alkyl group.

Fertile first step or" the reaction set forth above, the estrone' is suspended in an organic solvent such as ab: solute ethanol and treated with ethyl orthoformate. 'iher'e is thenadded a small amount of. mineral acid, such as sulfuric acid, and'the mixture is heatedat 40 C. for a short periodof time. Thereafter, additional ethyl orthoformate is added and the heating'is continued at a s'lightly: higher temperature for a shoitperiod of time until all of the estrone has gone into solution. The solution is then cooledand there is added slowlyan alkali such as potassium hydroxide, and thereafte' i, water. The solution now contains the cliacetal of estronewhich may be utilized for further reaction without separation.

For the production of the corresponding 3-ether as for example the methyl ether, there is added to the solution dimethyl sulfate dropwise, together with potassium hydroxide or other alkali in pellet form, the pH being maintained above 11. After the addition of the methyl sulfate water is added and an additionalquantity of alkali. The stirring is then continued for a short period of. time to. completethe hydrolysis of the excess of methyl sulfate. A crystalline product obtained is filtered, washed and dissolved in the organic solvent such as hexane containing pyridine, and .the solution concentrated. An oil is obtainedwhich consists of the 17-diacetal of the 3- methyl ether of'estrone which can be, used without further purification for. the next step or stored under refrigeration. For the reduction the l7-diacetal of the Ya-methyl ether of e'strone is dissolved in an organic solvent such as Dowanol 33, a glycol monoether'and the solution cooled to substantially below room temperature, as, for example, a tem'peratureof the order'of 3 C. There is then added anhydrous liquid ammonia and thereafter. an alkali metal in small pieces, such aslithium metal. Thereaction solution is stirred for approximately. one hour and thereafter there isadded water containing a small amount of hydroquino'ne. The product is filtered and .washed :to neutrality,as with water containing. a small amount of hydroquinone; The resultant product is the ,-3. -n;1ethy 1 ether l7-diacetal or" l9-nor A -androstadiene 3B-ol{ l7=one. The moist product of this step is. dissolved with stirring in an organic solvent such as hcnezene Ethyl alcohol is then added and the'temperatureofthe S0111: tion'adjusted to roomtemperature, or approximately'20 C. Thereafter, under vigorous agitation there is added only sutficient acid, preferably a dilute mineral acid such as sulfuric acid, in alcohol, in a quantity to produce a slightly acid condition, and the reaction is allowed to continue for a very short period of time as of the order of 16 seconds to one minute. It is found that with this short period of hydrolysis, which is terminated by the addition of a base such as potassium hydroxide, in water and alcohol, there is a quantitative selective hydrolysis of the protective diacetal grouping at 17, without affecting the ether group at 0-3. The resultant product is for example the 3-methox -19-nor-A -androstadiene-flone, which may be converted by known methods into 19- norethinyltestosterone. The present method possesses the decided advantage that the reduction of the aromatic system to the A -3-keto system is efiected with the protection This avoids the necessity of the regeneration of this group by subsequent oxidation which in practice was found to be a diificult and dangerous operation.

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I 100 g. of perfectly dry estrone suspended in 400 cc. of absolute ethanol was treated with 100 cc. of anhydrous ethyl orthoformate. Under mild stirring there was then added 1 .cc. of CJP. sulfuric acid and the mixture was heated at40 C. for 35 minutes. An additional 25 cc. of ethyl orthoformate was added and the heating was continuedat 55 C. for 20to-30 minutes 'until 'all of the estrone had gone into solution. Under external cool-' ing, there was added in the course of 15 minutes 50 g. of potassiumhydroxidein pellet form; the temperature is allowed to drop to 10 C. and then 400 cc. of water was added. r

Under strong stirring there was added simultaneously (a) 55 cc. of dimethyl sulfate at a rate of approximately 2 to 3 drops per second and (b) potassium hydroxide in pellets, in portions of 10 g. each-time the pH showed a tendency to'drop below 11. Afiterthe addition of all of the methyl sulfate, there is slowly added 400 cc. of water and the amount of potassium hydroxide is completed to 50 3., including the .one added previously. The stirring is continued for minutes to complete the hydrolysis of the excess of methyl sulfate. The crystalline product is ifiltered :(fi'om the filtrate approximately 5% of unreacted estrone can 'be recovered upon acidification), washed abundantly with slightly alkaline water and then' dissolved in 2 It. of hexane containing 10 cc. of pyridine. Thewater that may be present is separated in a s'eparatory funnel and the solution is dried over sodium sulfate. and

quickly concentrated at the temperature of the steam bath. Nearly at the end the temperature is lowered and the con centration is conducted under reduced pressure. Thus, an oil is. obtained, weighing approximatelyl35 gi, consisting oflthe l7.-diacetal of'the 3 -methylether ofestrone', which is usedfwithout further purification in the following step. it "the next' operation is not carried out immediately, it is; convenient 'to =k'eep the product in the refrigerator.

. Example II .5 The l 35 g. of the l7-diacetal of the B-methylether oi.

120 g. was thus obtained of the 3-methyl ether 17-diacetal of 19-nor-A -androstadien-3fl-ol-l7-one.

The moist product is dissolved with mild stirring in 550 cc. of benzene and, if necessary, water is added so the reaction mixture has a weight of 900 g. In case the mixture weighs more, some of the water is decanted until such weight is attained. 2 it. of 96% alcoholis added and .the'temperature'of the solution is adjusted to 20 C.

. Under strong stirring a solution of 4.4 cc. of GP. sulfuric acid in 50 cc. of alcohol is added. Aiter 16 seconds, a

solution is added of 15g. of U.S.P. potassium hydroxide in 10 cc. of water and 5.0 cc.zof alcohol. The mixture should remain slightly alkaline and the stirring is stopped to' avoid airing of. the solution. "The mixture then evaporatedtodryness under reduced pressure at the temperature of the steam .bath,-passing a slow stream of nitrogen through the solution. .At the end the stream of nitrogen is continued until the product has cooled and the product is kept under-, an-..atmosphere of nitrogen until it is used for the ,f ollowing operation. ,The V3- methoxy-lSknor-A -androstadien-l 7-one thus obtained had a melting point of 128-131 0., [din +199. I

We claim:

.1. A method torthe production of a 3 lower alkoxy 19 nor 4 andrlostadiene-lY-one which comprises '3 -methyl ether which-is prepared'by reaction-with dimethylsulfate and'the alkali metal is lithium. 3. The process of claim 1, wherein the selectivehydrol- V ysisof the-diacetal group of 3-lower alk oxy l7-diacetal of 19-nor-A -androstadieneB-ol-l7 one is performed by dissolving the startingmaterial in a mixture of benzene and ethyl alcohol, the solution thus, prepared is slightly acidified with sulfuric acid, and after a period of reaction of lessthan one minute the mixture is neutralized.

estron'eQoBtained 'in accordance with Example I, was

solu on wasgcooled' to 'a temperature of approxiinately'3 nder flstrong stirring in. anhydrous conditions there a, rained for 60 minutes and'tlien there .wa'sadded 10. 1t.

. ofriced 'distilled water containing 1% ocfihydroquinone.

oductf is filteredtaking care thatfit does notgo dissolved in. 4 ltr; of anhydrous Dowanol .33 and the f l rot lithium metaljin' small'pie'ces. Thestirring was dry n the funnel, and washed perfectly: to neutral with e we? o water e ema 1% m mm 4. A new compoundselected iromthe group consist ing' of the '.l7-diacetal of estrone,.the, 17-diace'tal of -3 lower alkoxy estrone and the. 17.'dia'cctal oi 3-lower alkoxy-l9-nor-A K -androstadien-l7rone..' a 5; The'17-diacetal of estrone. .1 6. The 17-diacetal of 3-methoxy estrone. 7. The '17-diacetal of 3-methoxy-19-nor-A -androstadien-l7-one; V.

7 References Cited in the file of. this patent .7 UNITED STATES PATENTS 2,550,702

Djerassi Feb. 12, 

1. A METHOD FOR THE PRODUCTION OF A 3-LOWER ALKOXY 19 - NOR - $2,5(10) - ANDROSTADIENE-17-ONE WHICH COMPRISES FORMING THE 17-DIACETAL OF ESTRONE BY REACTING ESTRONE WITH ETHYL ORTHOFORMATE, CONVERTING THE 17-DIACETAL OF ESTRONE INTO THE CORRESPONDING 3-LOWER ALKOXY ETHER, TREATING THE 3-LOWER ALKOXY ETHER WITH AN ALKALI METAL IN LIQUID AMMONIA TO REDUCE THE AROMATIC SYSTEM IN RING A TO A DIENE SYSTEM AND PREPARE THE 17-DIACETAL OF 3METHOXY-19-NOR-$2,5(10)-ANDROSTADIENE-17-ONE AND THEREAFTER SELECTIVELY HYDROLYZING THE DIACETAL GROUP AT C-17 BY A SHORT ACID TREATMENT. 